DESCRIPTION (application abstract) We propose to create an NDC for the Optical Control of Biological Function, to develop methods for rapidly turning select proteins in cells on and off with light. The strategies are broadly applicable across protein classes. The approach will be used for the non-invasive, quantitatively precise, control of the biomolecular dynamics of individual proteins, and for controlling signaling interactions between pairs of proteins. This approach can bring us closer to one of the central goals in biology: that of directly relating molecular events in particular cells to the function of an organ and the behavior of the organism. The developments hold promise in medicine for drug discovery, synthetic biology and the direct treatment of disease. We will develop three technology platforms: 1) chemical and molecular toolkits of modular parts for optical control and chemical integration into proteins, 2) viral delivery for installing photo-switchable proteins into cells, and 3) light delivery systems that make it possible to address these nanodvices in vivo. We will work to solve three engineering and clinical challenges: a) devise a general strategy for optical control over the functional state of individual proteins and the signaling interactions of pairs or groups of proteins;b) gain optical control over the signaling and enzymatic activity of cells in vitro, and c) adapt these approaches to treat retinal and cardiac pathologies. Members of the NDC will be organized into integrated, interdisciplinary teams. We expect three major outcomes. First, rounds of chemical synthesis, genetic engineering and biological testing will help develop the basic design for optical control of protein function, for the specific orthogonal attachment of light-gates, and for the optimal methods of molecular and light delivery in vivo. Second, we will employ light-gated proteins in animal models of human disease. Third, over 5 years we will formulate strategies for applications to cell-based drug screening and remote control switches for synthetic cells, and we will evaluate toxicity to guide the development of biocompatible devices that could be used in the clinic.